The synthetic pyrethroids are potent and widely used insecticides. Pyrethroids modify the ionic permeability of nerve membranes and produce distinctive poisoning syndromes in insects and in animals. The objective of this proposal is to elucidate the mechanisms underlying pyrethroid induced alterations in membrane excitability and synaptic function in the mammalian central nervous system. The proposed research will characterize the actions of two chemically and behaviorally distinct classes of pyrethroid insecticides on ion channel function, membrane depolarization and synaptic function in vitro. Pyrethroid action on voltage-gated and receptor-regulated ion channels will be determined by radiotracer ion flux measurements and neurotransmitter release studies in rat brain synaptosomes and brain slices. The information obtained from these studies will improve our understanding of the progression of events initiated by changes in ion channel function resulting in disturbances in synaptic transmission and culminating in the behavioral manifestations of poisoning. Chronic intoxication studies will provide information on the alterations in ion channel and synaptic function resulting from extended exposure to these insecticides and are important with respect to long term exposure in humans and other non-target organisms. Species differences in membrane excitability and ion channel function will be explored in rat and trout brain synaptosomes. Information obtained from these studies will improve our knowledge of the molecular basis of selective target organ toxicity of pyrethroid insecticides and is important in evaluating the environmental hazards associated with their use. These studies as a whole will advance our understanding of the neurotoxic actions of this important class of insecticides and improve our knowledge of the basic mechanisms of neuronal excitability.